rs1114167316

Variant names:

• chr3-4735314-T-C
• rs1114167316
• NM_001378452.1:c.5504T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001378452.1(ITPR1):​c.5504T>C​(p.Leu1835Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.61
• Publications: 7 publications found

Genes affected

ITPR1 (HGNC:6180): (inositol 1,4,5-trisphosphate receptor type 1) This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ITPR1 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 3-4735314-T-C is Pathogenic according to our data. Variant chr3-4735314-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 253023.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5504T>C	p.Leu1835Pro	missense_variant	Exon 44 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5459T>C	p.Leu1820Pro	missense_variant	Exon 43 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.5360T>C	p.Leu1787Pro	missense_variant	Exon 41 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.5315T>C	p.Leu1772Pro	missense_variant	Exon 40 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5504T>C	p.Leu1835Pro	missense_variant	Exon 44 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5480T>C	p.Leu1827Pro	missense_variant	Exon 44 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5477T>C	p.Leu1826Pro	missense_variant	Exon 44 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5462T>C	p.Leu1821Pro	missense_variant	Exon 43 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5459T>C	p.Leu1820Pro	missense_variant	Exon 43 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5432T>C	p.Leu1811Pro	missense_variant	Exon 41 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5360T>C	p.Leu1787Pro	missense_variant	Exon 41 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5315T>C	p.Leu1772Pro	missense_variant	Exon 40 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3266T>C	p.Leu1089Pro	missense_variant	Exon 24 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2804T>C	p.Leu935Pro	missense_variant	Exon 22 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2411T>C	p.Leu804Pro	missense_variant	Exon 20 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spinocerebellar ataxia type 29 Pathogenic:1

Aug 01, 2016

Research Group Niklas Dahl, Uppsala University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

We have identified a biallelic (homozygous) missense mutation in ITPR1 segregating with an autosomal recessive and early onset cerebellar syndrome. Heterozygous individuals are asymptomatic albeit with unequivocal cerebellar hypoplasia. Our findings add to the genetic complexity of Spinocerebellar ataxia (SCA) and broaden the correlations between ITPR1 variants and their clinical expression. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	.;.;.;.;.;.;M;.;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.6	D;D;.;D;.;.;.;.;D;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.012	D;D;.;D;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;.;D;.;.;.;.;D;.;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.;.
Vest4		0.99
MutPred		0.71		.;.;.;.;.;.;Gain of catalytic residue at L1835 (P = 0.0317);.;.;.;.;
MVP		0.98
MPC		0.79
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1114167316; hg19: chr3-4776998;